The present invention relates to a method for making isolongifolenone involving reacting (−)-isolongifolene with chromium hexacarbonyl and t-butyl hydroperoxide. The present invention also relates to the use of isolongifolenone to repel arthropods by treating an object or area with an arthropod repelling effective amount of isolongifolenone (and optionally a carrier or carrier material).
Diseases transmitted by blood-feeding arthropods are a serious threat to public health worldwide. More than 700 million cases of mosquito transmitted disease were reported annually (Shell, E. R., Atlantic Monthly, pp. 45-60, August 1997). Over 3 million people live under the threat of malaria, which kills over a million people each year (WHO World Malaria Report 2005, Roll Back Malaria, World Health Organization, UNICEF, http://rbm.who.int/wmr2005). In the United States, West Nile virus was transmitted by mosquitoes to more than 8,000 people from 1999-2005, resulting in over 780 deaths (DeBiasi, R. L., and K. L. TYLER, Nat. Clin. Pract. Neurol., 2:264-275 (2006)). N,N-Diethyltoluamide (Deet) is considered to be the best insect repellent ever developed and is the most widely used insect repellent worldwide with tens of millions of dollars in annual sales (Osimitz, T. G., and R. H. Grothaus, J. Am. Mosq. Control. Assoc., 11: 274-278 (1995)). However, Deet is a plasticizer and clinical literature reports the association of Deet with neurotoxicity in humans (Robbins, P. J., and M. G. Cherniack. J. Toxicol. Environ. Health, 18: 503-525 (1986)). Thus, there is a great need for effective alternatives to Deet.
We have found that isolongifolenone, which occurs in nature in trace amounts, is more effective than Deet in repelling ticks and deterring feeding mosquitoes. With high repellent efficiency, this compound will allow much wider application by the public and the military. Therefore, isolongifolenone has a great potential to displace Deet in the worldwide repellent marker.
Heretofore, isolongifolenone was most often obtained in large quantities by isomerization of longifolene, an abundant bridged tricyclic sesquiterpene found in turpentine oil from commercially available oleoresin of the Himalayan pine, Pinus longfolia Boxb (Ranganathan, R., et al., Tetrahedron, 26: 621-630 (1970)), to isolongifolene (U.S. Pat. No. 6,734,159) with subsequent oxidation by oxygen, air, or metal oxidants (Dauben, W. G., et al., J. Org. Chem., 34: 3587-3592 (1969); Lala, L. K., and J. B. Hall, J. Org. Chem., 35: 1172-1173 (1970); Mihelich, E. D., and D. J. Eickhoff, J. Org. Chem., 48: 4135-4137 (1983); Mequillin, F. J., and M. Wood, J. Chem. Res. Miniprint, 3: 0755-0757 (1997)). However, these oxidation methods involved long reaction times and gave poor yields and unwanted by-products that were difficult to separate from the desired compound, isolongifolenone, because of the great similarity of their physical and chemical properties to isolongifolenone (Prahlad, J. R., et al., Tetrahedron Lett. 5: 417-427 (1964); Shieh, B. J., et al., Nippon Kagaku Kaishi, 906-908 (1978); U.S. Pat. No. 5,030,739; U.S. Pat. No. 6,734,159).
We have developed a facile and efficient method for producing pure isolongifolenone in a short time and at high yield which will make it less expensive and allow wide availability of this chemical for various industrial and clinical usages and especially for programs aimed at controlling malaria, West Nile virus, Lyme disease, and other diseases by suppressing human blood-feeding by the arthropods that vector these diseases.